The most important set of findings in this study shows that 65% of participants experienced a moderate or severe level of IIB and that there is a broad set of variables associated with IIB. IIB is not merely a consequence of residual migraine symptoms, although they are relevant, but is also affected by socioeconomic status, income, and anxious avoidance of desirable activities. Therefore, a clinical approach that considers the patient’s symptoms as well as psychosocial context is likely to be the most successful for treatment optimization.

This study showed that migraine is often associated with substantial IIB in people with longstanding migraine; 65% of participants reported moderate or severe IIB. At the time people with migraine enrolled in this survey were treated with a CGRP-mAb (18 years after their first symptoms), the majority was still worried about their migraine episodes impacting personal and social activities. These worries were more common in those with CM. Socioeconomic status and income were among the explanatory variables for IIB based on both regression modeling and RF. Well-being, as assessed by the WHO-5, and the bespoke IIB questions regarding worry about exercise and fear of missing social obligations were important explanatory variables for IIB when considered in the context of all 37 variables based on RF techniques.

There were positive, significant correlations between the MIBS-4 and some of the variables of interest, particularly for “Worse migraine pain,” “Average migraine pain,” “Duration of an episode,” and “Presence of premonitory symptoms.” These observations are to be expected, as greater intensity of migraine episodes would reflect an increase in the burden of each episode. This fact could justify an increase in the MIBS-4 score, since MIBS-4 questions are much related to anticipation of upcoming attacks.

However, our analysis clearly showed that other variables besides migraine symptoms were associated with IIB. For example, there was a highly significant inverse correlation between the WHO-5 and MIBS-4 scores, indicating that patients who are most affected interictally by migraine have worse well-being scores.

Additionally, higher ASI-3 scores correlated significantly with higher MIBS-4 scores. The ASI-3 is not a measure of anxiety itself; rather, it is intended to capture sensitivity to anxiety in general. Anxiety sensitivity can be defined as the fear of anxiety-related arousal sensations, harmful physical, cognitive, and socially observable consequences that may be interpreted by the subject as having potential consequences such as death, insanity, or social rejection [27]. Thus, anxiety sensitivity can be an amplifier of anxiety: when subjects with high anxiety sensitivity become anxious, they fear their arousal sensations and become even more anxious [27]. In a study of 2350 individuals (644 without headache, 903 with migraine, and 803 with tension-type headache), the ASI-3 index was shown to be distinct between primary headache diagnostic groups and to predict symptomatology and disability and was associated with greater perceived susceptibility to headache triggers [32]. Higher scores from all three ASI-3 subscales were significant univariate predictors of higher headache-related disability, which showed a strong positive relationship with headache frequency and severity. Moreover, the variance in disability that was accounted for by anxiety sensitivity far exceeded that attributable to depression and anxiety combined [32]. Taken together, these data suggest that anxiety sensitivity is a key indicator of migraine burden as well as IIB.

Some variables related to the social determinants of health were shown to be associated with IIB. To the best of our knowledge, this study is the first to find a correlation between IIB, income, and education. Although some reports suggest that there is an increased risk of migraine among people with less education and lower income in the US [33,34,35], these findings have not been confirmed [36, 37]. Knowledge about the impact of socioeconomic factors on migraine prevalence is limited by the fact that most studies come from the wealthiest countries [38]. The social causation hypothesis, incorporating poorer diets and worse lifestyles, could explain these income-related migraine prevalence discrepancies [39]. In terms of migraine impact severity, the 2005 American Migraine Prevalence and Prevention survey showed that people with CM had significantly lower income levels, were less likely to be employed full-time, and were more likely to be occupationally disabled than those with EM [40]. Different epidemiological studies show that disability is greater with CM than with EM [41, 42].

A recent analysis of data from the OVERCOME (US) study found that the severity of migraine per migraine headache days is correlated to the severity of IIB, as measured by MIBS-4 [16]. Similarly, in our study the severity of IIB was significantly greater in participants with CM when compared to those with EM, even though the occurrence of IIB in both groups was nearly the same. Only 18% of participants with EM and 14% of those with CM reported no IIB. However, the machine-learning model suggested that the episodic vs chronic distinction was a noise variable that did not contribute to the variance in predicting IIB in patients. Thus, we suggest that migraine frequency alone should not be a consideration in determining IIB risk in patients with migraine.

The RF analyses identified predictive variables that required the support of less-important variables for an acceptable level of accuracy and revealed a complex, interrelated picture of predictors of IIB. We view the RF predictor set as perhaps more reliable than regression because RF makes no assumptions about the data and handles large numbers of potential predictors with ease, allowing an unlimited number of interactions. RF analyses are harder to interpret but may provide a more accurate picture of the complexity of IIB. Still, the regression results provided a consistent picture of IIB in this sample, and the variables identified across these techniques could be a fruitful source of hypotheses in future research.

Across all models, well-being was consistently the variable most strongly associated with IIB. Clearly, the presence of IIB contributes to worse well-being in patients with migraine. In other studies, semi-structured qualitative interviews [43] and online surveys [44] showed that migraine largely affects personal relations. For example, in the survey, 55% of people with migraine reported a fear of the next attack, and more than 80% felt compromised in their private, social, and professional lives [44]. People with migraine frequently experience poor understanding and consideration of the disease in their relationships [45]. Furthermore, studies have shown that the stigma associated with migraine is substantial [16, 45], which is consistent with our findings; many participants reported not seeking care because of fear of not being considered seriously by the healthcare provider. We suggest that at least part of the negative experiences imposed by migraine are associated with IIB, which is not well recognized, earning migraine the label of “the invisible disease” [45].

The linear regression analyses identified socioeconomic factors, level of well-being, selected migraine symptoms, and income as relevant predictors of IIB. The logistic regressions confirmed that disease characteristics (symptoms and duration) and income were important predictors of aspects of IIB. The RF analysis also confirmed the relevance of select disease symptoms as well as income to IIB and identified several other variables important to predicting IIB in people with migraine, especially socioeconomic status, and well-being. RF also revealed some additional nuances, such as anxiety sensitivity and the impact of migraine on work and relationships. We suggest that the ASI-3 be included in evaluating migraine patients and their treatment outcomes. We believe that the present study provides insights into how clinicians can appreciate that IIB is an important determinant of poor QoL in their patients. They can discuss treatment possibilities and outcomes more effectively with a greater understanding of IIB dimensions and predictors.

The study had some limitations that should be mentioned. Patients were required to answer the bespoke IIB questions based on experiences that took place during the year before galcanezumab initiation, and thus, their answers could have been affected by recall bias.​ Patients were required to answer the MIBS-4 questionnaire based on experiences that took place in the last 4 weeks and thus, their answers could have been affected by a reduction in symptoms due to treatment.​ However, this study was not designed to assess the effects of galcanezumab on IIB, no comparisons to placebo or pre-galcanezumab were conducted, and thus, no systematic effects of the mAb on IIB should be inferred here. Importantly, the participants had significant IIB, based on MIBS-4 scores, at the time of treatment with CGRP mAb. Men, ethnic minorities, people who have less education, and people with low socioeconomic status were underrepresented in our study. In the present study, females account for approximately 90% of respondents, compared with many observational studies reporting female to male ratios ranging from 2:1 to 3:1 [46,47,48]. This may limit the generalizability of the results, as there are sex differences in migraine symptoms and associated features. Women, compared with men, tend to have longer durations of migraine attacks and recovery time, more frequent accompanying symptoms, such as nausea, vomiting, photophobia, phonophobia, and allodynia, and they tend to have a greater burden of migraine [46, 47, 49, 50]. These differences might be partly attributed to the complex role that estrogens and progesterone play in regulating biological functions, including neuronal hyperexcitability and increasing responsiveness of brain structures that are important to migraine pathophysiology, such as the trigeminal nucleus caudalis [46, 51]. These factors may affect the IIB of migraine and can influence treatment outcomes, and merit further investigations.

To conclude, the results illustrate the importance of IIB as a concept to be considered in the medical care of people with migraine. If migraine can be called “the invisible disease,” the IIB must be considered “the invisible burden.” IIB in people with migraine is associated with worse well-being, higher sensitivity to anxiety, worse disease severity, lower income, and negative personal and social experiences. Ideally, the burden of the disease between attacks should also be considered in a holistic treatment approach, which does not ignore the significant IIB imposed by the disease, and merely highlight headache frequency, duration, and intensity.